It is known that pericellular fields and currents induced by an Extremely Low Frequency (ELF) electromagnetic field, whose frequency range is from 1 Hz to 300 Hz and perhaps up to 1000 Hz, induce within the cell certain membrane electrochemical events which are important for primary biologic signal transduction and amplification processes.
These biochemically mediated events then produce cytoplasmic second messengers and internal effectors such as free Ca++ and protein phosphorylases (kinases) which in turn trigger certain changes in the biosynthesis of macromolecules as well as bring about alterations in cellular growth differentiation and functional properties [1M. Blank, 1993].
Further, the possibility that S and ELF fields affect the DNA synthesis, DNA integrity, transcription and translation has been documented [2Liboff 1984, 3Tofani 1995, 4Goodman 1991, 5Phillips 1992].
A possible physical mechanism to account for some of the experimental findings is the direct effect on ions (i.e., Ca++) or on ligand binding at the cell membrane [6Liboff 1985, 7Chiabrera 1985, 8Lednev 1991, 9Blanchard 1994].
The possibility of influencing variations of Ca++ metabolism may lead to cell apoptosis (programmed cell death) [10Preston, 11Trump 1997].
Another physical interaction mechanism is related to the possibility of influencing the kinetics of appropriate cell signalling pathways of the cell (including calcium metabolism) through a field direct effect on electron-spin motion of atoms and molecules with unpaired electrons. This influencing may affect the recombination ratio of a spin correlated free radical pair and consequently on redox signalling [12Grundler 1992; 13Polk 1992; 14Walleczek and Budingher 1992; 15Adey 1993].
In particular, the spin singlet-triplet energetic level transition in a free radical is critical for increasing the recombination ratio of spin correlated free radical pairs.
The possibility for low level, non thermal (with intensity up to 30 mT) S and ELF magnetic fields to influence in vitro the kinetics and efficacy of radical pair reactions is known from magnetochemistry [16 Steiner 1989].
Naturally occurring free radicals have an oxygen- or nitrogen-based unpaired electron such as superoxide anion, hydroxyl radical and nitric oxide. These Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) can target proteins providing an obvious mechanistic explanation for free radicals-mediated signalling events. These events may influence growth factors, ion transport (i.e. Ca++ channels), transcription, apoptosis [17Lander 1997].
Apoptosis is a morphologically distinct form of programmed cell death that is connected in cell survival processes playing an important role during development, homeostasis, and in many diseases including cancer, acquired immunodeficiency syndrome, and neurodegenerative disorders, as well as in other diseases that similarly to those are characterised by altered cell survival processes. Apoptosis occurs through the activation of a cell-intrinsic suicide program. The basic genetic mechanism of apoptosis appears to be present in essentially all mammalian cells at all times, but the activation of this suicide program is regulated by many different signals that originate from both the intracellular and the extracellular environment.
Among all the genes involved in apoptosis regulation, the p53 gene is receiving much attention. This gene, which encodes a transcription factor and is common in many human cancers, mediates the cellular responses to some environmental damage. The p53 protein either can temporarily stop cell division, so that the cell can repair altered DNA, or can pilot the cell to an apoptotic death.
Published data support that p53 appears in apoptosis through a three step process: 1) transcriptional induction of redox-related genes: 2) the formation of reactive oxygen species and 3) the oxidative degradation of mitochondria components, culminating in cell death [18Polyak 1997].
In addition anti-oxidative agents are combined with drugs in the treatment of hypoxia tumour cells 19 [Walch, 1988] and in the influence of vascular growth factor 20[Amirkhosravi, 1998].
Moreover, published data are supporting the idea that pathological cells answer differently than normal cells to ELF fields stimuli. According to 21Cadossi [1992], lymphocytes from normal patients respond differently than lymphocytes from Down's syndrome, AIDS and chronic lymphocytic leukaemia patients when exposed to ELF fields (previously with mitogen).
It is also recognised that Ca++ influx across the membrane is influenced by ELF fields in leukaemic lymphocytes but not in normal lymphocytes [22Walleczek, 1996].
Altered cell survival processes come with electric disorders and different electrical behavior. In fact, rapidly proliferating and transformed cells have electrically depolarized cell membranes if compared with normal cells [23Binggeli, 1986; 24Marino 1994]. It has also been shown that epithelial cells lose their transepithelial potential during carcinogenesis [25Davies 1987; 26 Goller 1986; 27Capko, 1996]. This different electrical behavior of tumor cells compared with normal cells is the basis for a newly proposed cancer diagnostic modality [28Cuzick 1998]. In addition, the concentration of free radicals in transformed cells and tissues is higher than in non-transformed ones [29Szatrowski 1991; 30Shulyakovskaya 1993; 31Iwagaki 1995].
With reference to chemotherapy all efforts are devoted to the target of inducing cell apoptosis in vivo instead of killing them, through Signal Transduction Directed Therapy (STDT) of cancer [32Levin, 1998].
Signal Transduction is a functional term that connotes the translation of genetic information into signalling cascades that allow the cell to for example interpret and respond to external stimuli and/or duplicate itself Recent evidence suggests that alterations in the cell survival processes contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS. Treatments designed to specifically alter the apoptotic threshold connected with the survival processes mechanisms may have the potentiality to change the natural progression of some of these diseases [33Thompson, 1995].
High intensity electrical, electromagnetic and magnetic fields have been used to destroy pathological cells.
In 34U.S. Pat. No. 4,665,898 an apparatus is described in which animals having malignant cells are treated by means of a high intensity pulsed magnetic field, in order to neutralise/destroy malignant cells in a selective way. This apparatus produces magnetic thermal fields having intensity comprised between 1 Tesla up to 10 Tesla and reversing polarity in the range 5÷1000 Kilohertz. In the preferred embodiment the magnetic field intensity is set between 1 and 50 Tesla and in particular, in the examples, it is set at 5 Tesla and 8 Kilohertz up to 18 Tesla and 250 Kilohertz.
Different ELF, thermal, continuous or pulsed fields have been used for anti-cancer therapy in vitro [35Narita, 1997; 36Raylman, 1996].
In these cases the fields are of very high intensity, much higher than what people are allowed to be exposed by the safety standards, and may produce heating thus damaging normal tissues and cells.
ELF low intensity electromagnetic fields have been used as well to inhibit mitosis of malignant cells, such as in DE 4122380A1 and U.S. Pat. No. 5,156,587. However, these documents describe the use of sinusoidal fields only at a fixed net frequency and at a fixed intensity, with the possibility to sweep only a limited range of energy levels inside the cellular tissue.